Association between Operative Time and Short-Term Radical Cystectomy Complications.

INTRODUCTION: The aim of this study was to examine the relationship between duration of surgical intervention and postoperative complications in radical cystectomy (RC). We hypothesized that the complication rate increases with longer operative time. METHODS: We analyzed the National Surgical Quality Improvement Program database 2011-2017 to identify all patients who underwent RC. Clinicodemographic characteristics, operative time, and perioperative complications using the Clavien-Dindo Classification (CDC) were abstracted. We fit a generalized linear model with linear splines for operative time to analyze if the relationship between operative time and probability of complication changed over time. RESULTS: A total of 10,520 RC patients were identified with a mean operative time of 5.5 h (standard deviation 2.03). In 55% and 18.2%, any complication and major complications (CDC ≥3) occurred within 30 days postoperatively, respectively. The spline regression model for any complication showed an almost linear relationship between the complication rate and operative time, ranging from 55% at 2.5 h to 82% at 10 h. For major complications, the model revealed the inflection point (knot) at 4.5 h, which corresponds to the lowest complication rate with 15%. Operative times at the extremes of the distribution had higher complication rates: 17.5% if <2.5 h and 28% if >10 h. DISCUSSION/CONCLUSION: Operative time of RC is associated with postoperative complications. Though many factors impact the duration of surgery, surgeries that lasted between 4 and 5 h had trend toward the lowest complication rates. Attention to factors impacting operative time may allow surgeons to identify strategies for optimizing surgical care and reducing complications after RC.

Nephrotoxicity of immune checkpoint inhibitor therapy: a pharmacovigilance study.

BACKGROUND: Immune checkpoint inhibitor (ICI) therapy has demonstrated impressive clinical benefits across cancers. However, adverse drug reactions (ADRs) occur in every organ system, often due to autoimmune syndromes. We sought to investigate the association between ICI therapy and nephrotoxicity using a pharmacovigilance database, hypothesizing that inflammatory nephrotoxic syndromes would be reported more frequently in association with ICIs. METHODS: We analyzed VigiBase, the World Health Organization pharmacovigilance database, to identify renal ADRs (rADRs), such as nephritis, nephropathy and vascular disorders, reported in association with ICI therapy. We performed a disproportionality analysis to explore if rADRs were reported at a different rate with one of the ICI drugs compared with rADRs in the entire database, using an empirical Bayes estimator as a significance screen and defining the effect size with a reporting odds ratio (ROR). RESULTS: We found 2341 rADR for all examined ICI drugs, with a disproportionality signal solely for nephritis [ROR = 3.67, 95% confidence interval (CI) 3.34-4.04]. Examining the different drugs separately, pembrolizumab, nivolumab and ipilimumab + nivolumab combination therapy had significantly higher reporting odds of nephritis than the other ICI drugs (ROR = 4.54, 95% CI 3.81-5.4; ROR = 3.94, 95% CI 3.40-4.56; ROR 3.59, 95% CI 2.71-4.76, respectively). CONCLUSIONS: Using a pharmacovigilance method, we found increased odds of nephritis when examining rADRs associated with ICI therapy. Pembrolizumab, nivolumab and a combination of ipilimumab + nivolumab showed the highest odds. Clinicians should consider these findings and be aware of the increased risk of nephritis, especially in patients treated with pembrolizumab, when administering ICI therapy.

The impact of smoking on radical cystectomy complications increases in elderly patients.

BACKGROUND: Smoking, the most common risk factor for bladder cancer (BC), is associated with increased complications after radical cystectomy (RC), poorer oncologic outcomes, and higher mortality. The authors hypothesized that the effect of smoking on the probability of major complications increases with increasing age among patients who undergo RC. METHODS: The authors analyzed the American College of Surgeons National Surgical Quality Improvement Program database (2011-2017), identified all patients undergoing RC using Current Procedural Terminology codes, and formed two groups according to smoking status (active smoker and nonsmoker [included former and never-smokers]). Patient characteristics and 30-day postoperative complications using the Clavien-Dindo Classification (CDC) were assessed. A multivariable logistic regression model was constructed that included age, sex, race, body mass index, operative time, comorbidities, chemotherapy status, and type of diversion with major complications (CDC ≥III) as the outcome variable, and explored the interaction between age and smoking status. RESULTS: A total of 10,528 patients underwent RC, including 22.8% who were active smokers. The authors identified an interaction between age and smoking status (P = .045). Older patients were found to experience a stronger smoking effect than younger patients with regard to the probability of major complications. The risk of a major complication was the same for 50-year-old nonsmokers and smokers, but it increased from 17.8% to 21.7% for 70-year-old nonsmokers and smokers, respectively (P < .001). CONCLUSIONS: Up to 20% of patients who undergo RC are active smokers, and these individuals have an increased risk of major complications. The effect of smoking is stronger with increasing age; the difference with regard to complications for smokers versus nonsmokers was found to increase substantially, wherein older smokers are at an especially high risk of complications.

Access denied: The relationship between patient insurance status and access to high-volume hospitals.

BACKGROUND: Underinsured patients face significant barriers in accessing high-quality care. Evidence of whether access to high-volume surgical care is mediated by disparities in health insurance coverage remains wanting. METHODS: The authors used the National Cancer Data Base to identify all adult patients who had a confirmed diagnosis of breast, prostate, lung, or colorectal cancer during 2004 through 2016. The odds of receiving surgical care at a high-volume hospital were estimated according to the type of insurance using multivariable logistic regression analyses for each malignancy. Then, the interactions between study period and insurance status were assessed. RESULTS: In total, 1,279,738 patients were included in the study. Of these, patients with breast cancer who were insured by Medicare (odds ratio [OR], 0.75; P < .001), Medicaid (OR, 0.55; P < .001), or uninsured (OR, 0.50; P < .001); patients with prostate cancer who were insured by Medicare (OR, 0.87; P = .003), Medicaid (OR, 0.58; P = .001), or uninsured (OR, 0.36; P < .001); and patients with lung cancer who were insured by Medicare (OR, 0.84; P = .020), Medicaid (OR, 0.74; P = .001), or uninsured (OR, 0.48; P < .001) were less likely to receive surgical care at high-volume hospitals compared with patients who had private insurance. For patients with colorectal cancer, the effect of insurance differed by study period, and improved since 2011. For those on Medicaid, the odds of receiving care at a high-volume hospital were 0.51 during 2004 through 2007 and 0.99 during 2014 through 2016 (P for interaction = .001); for uninsured patients, the odds were 0.45 during 2004 through 2007 and 1.19 during 2014 through 2016 (P for interaction < .001) compared with patients who had private insurance. CONCLUSIONS: Uninsured, Medicare-insured, and Medicaid-insured patients are less likely to receive surgical care at high-volume hospitals. For uninsured and Medicaid-insured patients with colorectal cancer, the odds of receiving care at high-volume hospitals have improved since implementation of the Patient Protection and Affordable Care Act of 2010.

Racial differences in the treatment and outcomes for prostate cancer in Massachusetts.

BACKGROUND: Massachusetts is a northeastern state with universally mandated health insurance since 2006. Although Black men have generally worse prostate cancer outcomes, emerging data suggest that they may experience equivalent outcomes within a fully insured system. In this setting, the authors analyzed treatments and outcomes of non-Hispanic White and Black men in Massachusetts. METHODS: White and Black men who were 20 years old or older and had been diagnosed with localized intermediate- or high-risk nonmetastatic prostate cancer in 2004-2015 were identified in the Massachusetts Cancer Registry. Adjusted logistic regression models were used to assess predictors of definitive therapy. Adjusted and unadjusted survival models compared cancer-specific mortality. Interaction terms were then used to assess whether the effect of race varied between counties. RESULTS: A total of 20,856 men were identified. Of these, 19,287 (92.5%) were White. There were significant county-level differences in the odds of receiving definitive therapy and survival. Survival was worse for those with high-risk cancer (adjusted hazard ratio [HR], 1.50; 95% CI, 1.4-1.60) and those with public insurance (adjusted HR for Medicaid, 1.69; 95% CI, 1.38-2.07; adjusted HR for Medicare, 1.2; 95% CI, 1.14-1.35). Black men were less likely to receive definitive therapy (adjusted odds ratio, 0.78; 95% CI, 0.74-0.83) but had a 17% lower cancer-specific mortality (adjusted HR, 0.83; 95% CI, 0.7-0.99). CONCLUSIONS: Despite lower odds of definitive treatment, Black men experience decreased cancer-specific mortality in comparison with White men in Massachusetts. These data support the growing body of research showing that Black men may achieve outcomes equivalent to or even better than those of White men within the context of a well-insured population. LAY SUMMARY: There is a growing body of evidence showing that the excess risk of death among Black men with prostate cancer may be caused by disparities in access to care, with few or no disparities seen in universally insured health systems such as the Veterans Affairs and US Military Health System. Therefore, the authors sought to assess racial disparities in prostate cancer in Massachusetts, which was the earliest US state to mandate universal insurance coverage (in 2006). Despite lower odds of definitive treatment, Black men with prostate cancer experience reduced cancer-specific mortality in comparison with White men in Massachusetts. These data support the growing body of research showing that Black men may achieve outcomes equivalent to or even better than those of White men within the context of a well-insured population.

Where Is the Value in Ambulatory Versus Inpatient Surgery?

OBJECTIVE: The aim of this study was to estimate the effect of index surgical care setting on perioperative costs and readmission rates across 4 common elective general surgery procedures. SUMMARY BACKGROUND DATA: Facility fees seem to be a driving force behind rising US healthcare costs, and inpatient-based fees are significantly higher than those associated with ambulatory services. Little is known about factors influencing where patients undergo elective surgery. METHODS: All-payer claims data from the 2014 New York and Florida Healthcare Cost and Utilization Project were used to identify 73,724 individuals undergoing an index hernia repair, primary total or partial thyroidectomy, laparoscopic cholecystectomy, or laparoscopic appendectomy in either the inpatient or ambulatory care setting. Inverse probability of treatment weighting-adjusted gamma generalized linear and logistic regression was employed to compare costs and 30-day readmission between inpatient and ambulatory-based surgery, respectively. RESULTS: Approximately 87% of index surgical cases were performed in the ambulatory setting. Adjusted mean index surgical costs were significantly lower among ambulatory versus inpatient cases for all 4 procedures (P < 0.001 for all). Adjusted odds of experiencing a 30-day readmission after thyroidectomy [odds ratio (OR) 0.70, 95% confidence interval (CI), 0.53-0.93; P = 0.03], hernia repair (OR 0.28, 95% CI, 0.20-0.40; P < 0.001), and laparoscopic cholecystectomy (OR 0.37, 95% CI, 0.32-0.43; P < 0.001) were lower in the ambulatory versus inpatient setting. Readmission rates among ambulatory versus inpatient-based laparoscopic appendectomy were comparable (OR 0.63, 95% CI, 0.31-1.26; P = 0.19). CONCLUSIONS: Ambulatory surgery offers significant costs savings and generally superior 30-day outcomes relative to inpatient-based care for appropriately selected patients across 4 common elective general surgery procedures.

Lessons from Pharmacovigilance: Pulmonary Immune-Related Adverse Events After Immune Checkpoint Inhibitor Therapy.

PURPOSE: To characterize pulmonary toxicities associated with the use of novel immune checkpoint inhibitors METHODS: Adverse event reports from immune checkpoint inhibitors targeting PD-1/L1 and CTLA-4 were captured from the W.H.O pharmacovigilance database (VigiBase) up until Dec. 31st 2019 and were analyzed to evaluate for measures of association between the use of immune checkpoint inhibitors and pulmonary toxicities. Disproportionality analysis using both frequentist and Bayesian approaches were used to detect signals between pulmonary immune-related adverse events and the use of these agents. RESULTS: A total of 9202 adverse pulmonary immune checkpoint inhibitor-related events were captured up until 2019. Adverse pulmonary events were compromised of 1305 airway, 18 alveolar, 5491 interstitial, 898 pleural, 560 vascular and 939 non-specific pulmonary events. We found a common association between all immune checkpoint inhibitors studied and pneumonitis, interstitial lung disease, pulmonary embolism and respiratory failure. We also noted other associations between immune checkpoint inhibitors, however not as uniformly across agents. Most of these immune-related adverse drug reactions were noted to be severe and accounted for a significant source of mortality in the reported cases. CONCLUSION: Immune checkpoint inhibitors are associated with a spectrum of inflammatory pulmonary toxicities. The breadth of pulmonary complications and prevalence may be underappreciated with the use of these agents.

Association of the hospital readmission reduction program with readmission and mortality outcomes after coronary artery bypass graft surgery.

The Affordable Care Act established the Hospital Readmissions Reduction Program (HRRP) to reduce payments to hospitals with excessive readmissions in an effort to link payment to the quality of hospital care. Prior studies demonstrating an association of HRRP implementation with increased mortality after heart failure discharges have prompted concern for potential unintended adverse consequences of the HRRP. We examined the impact of these policies on coronary artery bypass graft (CABG) surgery outcomes using the Nationwide Readmissions Database and found that, in line with previously observed readmission trends for CABG, readmission rates continued to decline in the era of the HRRP, but that this did not come at the expense of increased mortality. These results suggest that inclusion of surgical procedures, such as CABG in the HRRP might be an effective cost-reducing measure that does not adversely affect quality of hospital care.

The impact of underinsurance on bladder cancer diagnosis, survival, and care delivery for individuals under the age of 65 years.

BACKGROUND: Health insurance is a key mediator of health care disparities. Outcomes in bladder cancer, one of the costliest diseases to treat, may be especially sensitive to a patient's insurance status. METHODS: The Surveillance, Epidemiology, and End Results registry and the National Cancer Data Base were used to identify individuals younger than 65 years who were diagnosed with bladder cancer from 2007 to 2014. The associations between the insurance status (privately insured, insured by Medicaid, or uninsured) and the following outcomes were evaluated: diagnosis with advanced disease, cancer-specific survival, delay in treatment longer than 90 days, treatment in a high-volume hospital, and receipt of neoadjuvant chemotherapy (NAC). RESULTS: Compared with those with private insurance, uninsured and Medicaid-insured individuals were nearly twice as likely to receive a diagnosis of muscle-invasive bladder cancer (odds ratio [OR] for uninsured individuals, 1.90; 95% confidence interval [CI], 1.70-2.12; OR for Medicaid-insured individuals, 2.03; 95% CI, 1.87-2.20). They were also more likely to die of bladder cancer (adjusted hazard ratio [AHR] for uninsured individuals, 1.49; 95% CI, 1.31-1.71; AHR for Medicaid-insured individuals, 1.61; 95% CI, 1.46-1.79). Delays in treatment longer than 90 days were more likely for uninsured (OR, 1.36; 95% CI, 1.12-1.65) and Medicaid-insured individuals (OR, 1.22; 95% CI, 1.03-1.44) in comparison with the privately insured. Uninsured patients had lower odds of treatment at a high-volume facility, and Medicaid-insured patients had lower odds of receiving NAC (P < .001 for both). CONCLUSIONS: Compared with privately insured individuals, uninsured and Medicaid-insured individuals experience worse prognoses and poorer care quality. Expanding high-quality insurance coverage to marginalized populations may help to reduce the burden of this disease.

Differences in survival and impact of adjuvant chemotherapy in patients with variant histology of tumors of the renal pelvis.

BACKGROUND: The impact of variant histologies on overall survival (OS), as well as their influence on the response to neoadjuvant and adjuvant chemotherapy (AC) is well studied in patients diagnosed with bladder cancer. However, little is known about tumors with variant histologies of the upper urinary tract. The objective of this study was to assess the survival of the predominant variant histologies of tumors of the renal pelvis (RPT) after surgical intervention, and to examine the influence of AC on the OS of the different variant histologies. METHODS: We identified 21,318 patients with RPT undergoing surgical intervention using the National Cancer Database for the period 2004-2015. We employed multivariable Cox proportional hazards regression models and Kaplan-Meier curves to evaluate the OS according to variant histology. Separate multivariable Cox regression models were used to assess the specific effect of AC on OS of the histological subgroups. RESULTS: The majority of patients were diagnosed with pure urothelial carcinoma (PUC) (96.1%). Overall, 826 patients were diagnosed with variant histologies (adenocarcinoma N = 298, squamous cell carcinoma N = 291, sarcomatoid N = 137, others N = 100). Compared to PUC, adenocarcinomas showed longer OS (HR 0.76, 95% confidence interval (CI) 0.62-0.94, p = 0.01), while sarcomatoid tumors had shorter OS (HR 1.59, 95% CI 1.12-2.26, p = 0.011). A subgroup analysis of patients undergoing AC showed a survival benefit in patients with PUC (HR 0.81, 95% CI 0.73-0.9, p < 0.001). CONCLUSION: We found that variant histologies of upper urinary tract carcinomas exhibit different survival rates and that AC was only associated with an OS benefit in patients with PUC.

Minimally invasive cancer surgery is associated with a lower risk of venous thromboembolic events.

BACKGROUND: Venous thromboembolism (VTE) is a significant source of postoperative morbidity and mortality in patients undergoing common oncologic procedures. We sought to estimate the effect of surgical approach on the risk of developing a VTE. METHODS: IBM Watson Health Marketscan Database was used to conduct this retrospective study. In total, 12 938 patients who underwent either a radical prostatectomy, partial colectomy, or hysterectomy via a minimally invasive or open approach. We used a propensity-weighted logistic regression analysis to assess the independent effect of surgical approach on VTE. The primary outcome of interest was the 90-day rate of VTE after surgery. RESULTS: Patients undergoing minimally invasive surgery across all three surgical procedures were noted to have a lower odds of developing a VTE: (radical prostatectomy, odds ratio [OR]: 0.667, 95% confidence interval [CI]: 0.500-0.891; P = .006 |partial colectomy: OR, 0.620, 95% CI: 0.477-0.805; P < .001| hysterectomy: OR, 0.549 95% CI: 0.353-0.854; P = .008). CONCLUSION: We found that a minimally invasive approach was associated with significantly lower odds of VTE compared with undergoing the same open procedure. This study highlights how surgical approach may be an independent risk factor for development of VTE and may elucidate potential risk mitigation strategy.

Association of surgical approach and prolonged opioid prescriptions in patients undergoing major pelvic cancer procedures.

BACKGROUND: The rise in deaths attributed to opioid drugs has become a major public health problem in the United States and in the world. Minimally invasive surgery (MIS) is associated with a faster postoperative recovery and our aim was to investigate if the use of MIS was associated with lower odds of prolonged opioid prescriptions after major procedures. METHODS: Retrospective study using the IBM Watson Health Marketscan® Commerical Claims and Encounters Database investigating opioid-naïve cancer patients aged 18-64 who underwent open versus MIS radical prostatectomy (RP), partial colectomy (PC) or hysterectomy (HYS) from 2012 to 2017. Propensity weighted logistic regression analyses were used to estimate the independent effect of surgical approach on prolonged opioid prescriptions, defined as prescriptions within 91-180 days of surgery. RESULTS: Overall, 6838 patients underwent RP (MIS 85.5%), 4480 patients underwent PC (MIS 61.6%) and 1620 patients underwent HYS (MIS 41.8%). Approximately 70-80% of all patients had perioperative opioid prescriptions. In the weighted model, patients undergoing MIS were significantly less likely to have prolonged opioid prescriptions in all three surgery types (Odds Ratio [OR] 0.737, 95% Confidence Interval [CI] 0.595-0.914, p = 0.006; OR 0.728, 95% CI 0.600-0.882, p = 0.001; OR 0.655, 95% CI 0.466-0.920, p = 0.015, respectively). CONCLUSION: The use of the MIS was associated with lower odds of prolonged opioid prescription in all procedures examined. While additional studies such as clinical trials are needed for further confirmation, our findings need to be considered for patient counseling as postoperative differences between approaches do exist.

Impact of adjuvant chemotherapy in patients with adverse features and variant histology at radical cystectomy for muscle-invasive carcinoma of the bladder: Does histologic subtype matter?

BACKGROUND: The use of adjuvant chemotherapy (AC) in pure urothelial carcinoma of the bladder is established. Regarding variant histology, there is a gap in knowledge concerning the optimal treatment after radical cystectomy (RC). The objective of this study was to assess the effect of AC on overall survival (OS) in patients who had pure urothelial carcinoma, urothelial carcinoma with concomitant variant histology, or another pure variant histology. METHODS: Within the National Cancer Data Base, 15,397 patients who underwent RC for nonmetastatic, localized carcinoma of the bladder and had positive lymph nodes (T2N+) or locally advanced stage (≥T3N0/N+) were identified, excluding those who had previously received neoadjuvant chemotherapy. Multivariable Cox regression models were used to examine the specific effect of AC on OS stratified by each distinct histologic subtype, including pure urothelial carcinoma, micropapillary or sarcomatoid differentiation, squamous cell carcinoma, adenocarcinoma, and neuroendocrine tumors. To account for immortal time bias, Cox regression analyses and Kaplan-Meier analyses were conducted with a landmark at 3 months. RESULTS: In multivariable landmark analyses, AC compared with initial observation was associated with an OS benefit for patients who had pure urothelial carcinoma (hazard ratio, 0.87; 95% confidence interval, 0.82-0.91), whereas no differences were observed with regard to those who had variant histology. CONCLUSIONS: Multivariable Cox regression landmark analysis revealed a survival benefit from AC for patients with a pure urothelial carcinoma. However, a survival benefit of AC for patients who had urothelial carcinoma with concomitant variant histology or other pure variant histology was not demonstrated.

Disparities in burden of disease in patients with rheumatoid arthritis across racial and ethnic groups.

To examine racial/ethnic differences in rheumatoid arthritis (RA) disease burden and change in clinical outcomes over time. We included CorEvitas Rheumatoid Arthritis Registry patients from two time periods (2013-2015 and 2018-2020). Clinical Disease Activity Index (CDAI) (as a continuous measure and as a dichotomous measure) and the Health Assessment Questionnaire-Disability Index (HAQ-DI) were assessed at each visit. Marginal means and their corresponding 95% confidence interval (CI) by race/ethnicity were estimated for each outcome using adjusted mixed effects linear and logistic regression models. Overall and pairwise tests were conducted to detect differences between race/ethnicity groups. Of 9,363 eligible patients (8,142 White, 527 Black, 545 Hispanic, 149 Asian), most (76%-85%) were female. At Visit 1, the mean disease duration ranged from 9.8-11.8 years. Estimated CDAI was significantly higher for Hispanics compared to Whites at Visit 1 (11.1 vs. 9.9; pairwise P = 0.033) and Visit 2 (9.2 vs. 8.0, pairwise P = 0.005). Disease activity improved over the 5-year study period among all race/ethnicity groups, though Hispanics improved less than Whites. Disease activity improved over the 5-year period across all racial/ethnicity groups, and disparities between racial/ethnicity groups in disease activity and functional status did persist over time, suggesting that further effort is needed to understand the drivers of these discrepancies to close this race/ethnicity gap. Key Points • Disease activity improved over the 5-year period across all racial and ethnic groups. • Disparities between racial and ethnic groups in disease activity and functional status did persist over time, suggesting that further effort is needed to understand the drivers of these discrepancies and close this racial gap.

Are work relative value units correlated with operative duration of common surgical procedures?

OBJECTIVES: Work relative value units (wRVUs) quantify physician workload. In theory, higher wRVU assignments for procedures recognize an increase in complexity and time required to complete the procedure. The fairness of wRVU assignment is debated across specialties, with some surgeons arguing that reimbursement may be unfairly low for longer, more complex cases. For this reason, we sought to assess the correlation of wRVUs with operative time in commonly performed surgeries. STUDY DESIGN: We analyzed the National Surgical Quality Improvement Program database, selecting the 15 most performed surgical procedures across specialties in a 90-day global period, using Current Procedural Terminology codes. METHODS: Calculation and comparison of mean operative time and mean wRVUs were performed for each of the 15 procedures. Cases with missing values for wRVUs or operative time and cases with an operative time of less than 15 minutes were excluded. The Spearman correlation coefficient was calculated to evaluate the strength of correlation between operative duration and wRVUs. RESULTS: A total of 1,994,394 patients met criteria for analysis. The lowest mean wRVU was 7.78 (95% CI, 7.77-7.78) for inguinal hernia repair; the highest was 43.50 (95% CI, 43.37-43.60) for pancreatectomy. The shortest mean operative time was 51.0 (95% CI, 50.8-51.1) minutes for appendectomy; the longest was for pancreatectomy at 324.6 (95% CI, 323.2-326.0) minutes. The Spearman correlation coefficient was 0.81. CONCLUSIONS: In our analysis, we found a strong correlation between operative duration and wRVU assignment. Thus, the reimbursement of physicians depending on wRVUs is fair for the most commonly performed surgical procedures across specialties.

Immune checkpoint inhibitor monotherapy is associated with less cardiac toxicity than combination therapy.

BACKGROUND: Treatment options for many cancers include immune checkpoint inhibitor (ICI) monotherapy and combination therapy with impressive clinical benefit across cancers. We sought to define the comparative cardiac risks of ICI combination and monotherapy. METHODS: We used VigiBase, the World Health Organization pharmacovigilance database, to identify cardiac ADRs (cADRs), such as carditis, heart failure, arrhythmia, myocardial infarction, and valvular dysfunction, related to ICI therapy. To explore possible relationships, we used the reporting odds ratio (ROR) as a proxy of relative risk. A lower bound of a 95% confidence interval of ROR &gt; 1 reflects a disproportionality signal that more ADRs are observed than expected due to chance. RESULTS: We found 2278 cADR for ICI monotherapy and 353 for ICI combination therapy. Combination therapy was associated with significantly higher odds of carditis (ROR 6.9, 95% CI: 5.6-8.3) versus ICI monotherapy (ROR 5.0, 95% CI: 4.6-5.4). Carditis in ICI combination therapy was fatal in 23.4% of reported ADRs, compared to 15.8% for ICI monotherapy (P = 0.058). CONCLUSIONS: Using validated pharmacovigilance methodology, we found increased odds of carditis for all ICI therapies, with the highest odds for combination therapy. Given the substantial risk of severe ADR and death, clinicians should consider these findings when prescribing checkpoint inhibitors.

Trends in Surgical Volume in the Military Health System-A Potential Threat to Mission Readiness.

INTRODUCTION: The Military Health System (MHS) is tasked with a dual mission both to provide medical services for covered patients and to ensure that its active duty medical personnel maintain readiness for deployment. Knowledge, skills, and attitudes (KSA) is a metric evaluating the transferrable skills incorporated into a given surgery or medical procedure that are most relevant for surgeons deployed to a theatre of war. Procedures carrying a high KSA value are those utilizing skills with high relevance for maintaining deployment readiness. Given ongoing concerns regarding surgical volumes at MTFs and the potential adverse impact on military surgeon mission readiness were high-value surgeries to be lost to the civilian sector, we evaluated trends in the setting of high-value surgeries for beneficiaries within the MHS. METHODS: We retrospectively analyzed inpatient admissions data from MTFs and TRICARE claims data from civilian hospitals, 2005-2019, to identify TRICARE-covered patients covered under "purchased care" (referred to civilian facilities) or receiving "direct care" (undergoing treatment at MTFs) and undergoing seven high-value/high-KSA surgeries: colectomy, pancreatectomy, hepatectomy, open carotid endarterectomy, abdominal aortic aneurysm (AAA) repair, esophagectomy, and coronary artery bypass grafting (CABG). Overall and procedure-specific counts were captured, MTFs were categorized into quartiles by volume, and independence between trends was tested with a Cochran-Armitage test, hypothesizing that the proportion of cases referred for purchased care was increasing. RESULTS: We captured 292,411 cases, including 7,653 pancreatectomies, 4,177 hepatectomies, 3,815 esophagectomies, 112,684 colectomies, 92,161 CABGs, 26,893 AAA repairs, and 45,028 carotid endarterectomies. The majority of cases included were referred for purchased care (90.3%), with the proportion of cases referred increasing over the study period (P < .01). By procedure, all cases except AAA repairs were increasingly referred for treatment over the study period (all P < .01, except esophagectomy P = .04). On examining volume, we found that even the highest-volume-quartile MTFs performed a median of less than one esophagectomy, hepatectomy, or pancreatectomy per month. The only included procedure performed once a month or more at the majority of MTFs was CABG. CONCLUSION: On examining volume and referral trends for high-value surgeries within the MHS, we found low surgical volumes at the vast majority of included MTFs and an increasing proportion of cases referred to civilian hospitals over the last 15 years. Our findings illustrate missed opportunities for maintaining the mission readiness of military surgical personnel. Prioritizing the recapture of lost surgical volume may improve the surgical teams' mission readiness.

Cardiovascular toxicities associated with abiraterone compared to enzalutamide-A pharmacovigilance study.

BACKGROUND: Androgen deprivation therapy (ADT) is standard-of-care for advanced prostate cancer. Studies have generally found increased cardiovascular risks associated with ADT, but the comparative risk of newer agents is under-characterized. We defined the cardiac risks of abiraterone and enzalutamide, using gonadotropic releasing hormone (GnRH) agonists to establish baseline ADT risk. METHODS: We used VigiBase, the World Health Organization pharmacovigilance database, to identify cardiac adverse drug reactions (ADRs) in a cohort taking GnRH agonists, abiraterone, or enzalutamide therapy for prostate cancer, comparing them to all other patients. To examine the relationship, we used an empirical Bayes estimator to screen for significance, then calculated the reporting odds ratio (ROR), a surrogate measure of association. A lower bound of a 95% confidence interval (CI) of ROR > 1 reflects a disproportionality signal that more ADRs are observed than expected due to chance. FINDINGS: We identified 2,433 cardiac ADRs, with higher odds for abiraterone compared to all other VigiBase drugs for overall cardiac events (ROR 1•59, 95% CI 1•48-1•71), myocardial infarction (1•35, 1•16-1•58), arrythmia (2•04, 1•82-2•30), and heart failure (3•02, 2•60-3•51), but found no signal for enzalutamide. Patients on GnRH agonists also had increased risk of cardiac events (ROR 1•21, 95% CI 1•12-1•30), myocardial infarction (1•80, 1•61-2•03) and heart failure (2•06, 1•76-2•41). INTERPRETATION: We found higher reported odds of cardiac events for abiraterone but not enzalutamide. Our data may suggest that patients with significant cardiac comorbidities may be better-suited for therapy with enzalutamide over abiraterone. FUNDING: None.